The incidence of melanoma is approximately 60.000 per year in the US. Approximately 10% of patients will present with high risk stage II disease (10 year survival of app. 55%) [Balch C M, Buzaid A C, Soong S J et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19(16):3635-3648] and approximately 20% of patients with any stage II or III. For patients with stage II and III melanoma survival rates are not satisfactory with currently available treatment options.
Proleukin® is the brand name for a prescription form of recombinant human interleukin-2 (rhIL-2). It is labeled for treatment of adults with metastatic melanoma and metastatic kidney cancer. Proleukin® has been used for over 15 years in the treatment of metastatic melanoma and metastatic kidney cancer (renal cell carcinoma). Interleukin-2 was first approved by the FDA for treatment of stage IV melanoma and renal cell carcinoma in 1992. The use of interleukin-2 has been extensively studied in patients with unresectable AJCC [The American Joint Committee on Cancer “AJCC”] stage III and stage IV melanoma with infrequent but sometimes impressive clinical results.
Experiences gained from the use of Interleukin-2 in patients with stage IV renal cell carcinoma, stage IV malignant melanoma and unresectable stage III malignant melanoma demonstrates that Interleukin-2 has therapeutic potential in these patient groups. The frequency of clinical responses is however limited with objective response rates of up to 20% and with approximately 5% of patients achieving complete responses. Atkins M B, Lotze M T, Dutcher J P et al., High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993, J Clin Oncol 1999; 17(7):2105-2116; Rosenberg S A, Yang J C, White D E, Steinberg S M., Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response, Ann Surg 1998; 228(3):307-319.8, 9. In patients where complete responses are obtained, these responses have frequently shown to be durable with duration of responses exceeding 10 years. Rosenberg S A, Yang J C, White D E, Steinberg S M., Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response, Ann Surg 1998; 228(3):307-319. High dose IL-2 treatment, however, is associated with substantial toxicities, which has limited its clinical use. For example, high dose bolus interleukin 2 (IL-2) used in the treatment of metastatic melanoma and renal cell carcinoma is known to cause vascular leak syndrome and serious cardiac toxicities, including myocarditis in a significant fraction of the patients.
Only a limited number of publications contemplate potential neoadjuvant application of cytokines for the treatment of Stage II and III melanoma. For example, Granolucyte Macrophage Stimulating Factor (GM-CSF) has been administered neoadjuvantly to patients with stage I melanoma in order to examine responsive effects on dendritic cells and T-cell responses. See Vuylsteke R J C L, Molenkamp B G, Gietema H A et al., Local administration of granulocyte/macrophage colony-stimulating factor increases the number and activation state of dendritic cells in the sentinel lymph node of early-stage melanoma, Cancer Res 2004; 64(22):8456-8460; Molenkamp B G, Vuylsteke R J C L, van Leeuwen P A M et al., Matched skin and sentinel lymph node samples of melanoma patients reveal exclusive migration of mature dendritic cells, AM J PATHOL 2005; 167(5):1301-1307.; Vuylsteke R J C L, Molenkamp B G, van Leeuwen P A M et al. Tumor-specific CD8+ T cell reactivity in the sentinel lymph node of GM-CSF-treated stage I melanoma patients is associated with high myeloid dendritic cell content, Clin Cancer Res 2006; 12(9):2826-2833. However, direct assessment of anti-tumor effects within the lymph nodes following local neo-adjuvant administration of immuno-modulatory compounds have not been performed (to our knowledge). Toll like receptor-9 (CpG-7909/PF-3512676) has also been explored using local administration with clear biological effects observed within the draining lymph nodes. Molenkamp B G, Sluijter B J, van Leeuwen P A et al., Local Administration of PF-3512676 CpG-B Instigates Tumor-Specific CD8+ T-Cell Reactivity in Melanoma Patients, Clinical cancer research: an official journal of the American Association for Cancer Research, 2008; 14(14):4532-4542; Sluijter B, Molenkamp B, deGruijl T et al. The effects of pre-operative administration of CpG 7909 on dendritic and T cell subsets in the sentinel lymph node of stage I/II melanoma patients, Melanoma research 16, suppl. 1, S43-S44. 2006 (Abstract). Direct assessment of anti-tumor effects within the tumor-draining lymph nodes following local administration of immuno-modulatory agents has not been explored in a neo-adjuvant setting in patients with stage A clinical trial in patients with stage is currently ongoing with patients receiving a vaccination with melanoma antigen peptides in combination with low doses of IL-2 (Clinical trials.gov; NCT00112242). This trial is however not designed to inject IL-2 in the tumor draining lymph nodes. Interleukin-2 has been administered intra-lesionally in patients with stage IV disease and a local high response rate was observed. Radny P, Caroli U M, Bauer J et al., Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 2003; 89(9):1620-1626. However this trial was undertaken in patients with advanced disease and consequently limited systemic responses were observed.
U.S. 2002146397A is purportedly directed to vaccine immunotherapy for immune suppressed patients purportedly teaches a method treating cancer and other persistent lesions includes the steps of administering an effective amount of a natural cytokine mixture as an adjuvant to endogenous or exogenous administered antigen to the cancer or other persistent lesions.
U.S. 2009220472A is purportedly directed to a method comprising identification of tumor-reactive T-lymphocytes from a patients sentinel and/or metinel lymph nodes draining a malignant melanoma or a metastasis there from, resection of the one or more nodes and, optionally all or part of the tumor or metastasis, isolation of tumor-reactive T-lymphocytes from said lymph nodes, in vitro expansion of said tumor-reactive T-lymphocytes, and administration of the thus obtained tumor-reactive T-lymphocytes to the patient, wherein the T-lymphocytes are CD4+ helper and/or CD8+ T-lymphocytes purportedly has therapeutic potential.
U.S. 2009297489A is purportedly directed to a method for expansion and activation of tumor-reactive lymphocytes, in particular CD4+ helper and/or CD8+ T-lymphocytes, which may be used for treating and/or preventing cancer. The method purportedly comprises a first phase of stimulating tumor-reactive CD4+ T helper and/or CD8+ T-lymphocytes with tumor-derived antigen together with at least one substance having agonistic activity towards the IL-2 receptor to promote survival of tumor-reactive CD4+ T helper and/or CD8+ T-lymphocytes; and a second phase of activating and promoting growth of tumor-reactive CD4+ T helper and/or CD8+ T-lymphocytes, wherein the second phase is initiated when the CD25 cell surface marker (or IL-2R marker) is down-regulated on CD4+ T helper and/or CD8+ T-lymphocytes.
U.S. 2003180254A is purportedly directed to a method for activating a mammalian immune system entailing a series of IL-2 administrations that are effected intermittently over an extended period. Each administration of IL-2 is purportedly sufficient to allow spontaneous DNA synthesis in peripheral blood or lymph node cells of the patient to increase and peak, and each subsequent administration follows the preceding administration in the series by a period of time that is sufficient to allow IL-2 receptor expression in peripheral or lymph node blood of the patient to increase, peak and then decrease to 50 percent of peak value.
Arora A, Su G, Mathiowitz E, Reineke J, Chang A E, Sabel M S., Neoadjuvant intratumoral cytokine-loaded microspheres are superior to postoperative autologous cellular vaccines in generating systemic anti-tumor immunity, J Surg Oncol. 2006 Oct. 1; 94(5):403-12 discusses a treatment of intratumoral IL-12 and TNF-alpha loaded PLAM which purportedly led to both local eradication of tumor and the induction of specific anti-tumor T-cells in the lymph nodes and spleens, resulting in memory immune response. Neoadjuvant treatment was said to be significantly superior to postoperative autologous cellular vaccines using IL-12 and TNF-alpha PLAM.